Obesity is the largest growing health problem in the western world. Despite considerable effort by the scientific and health care professions to understand and successfully treat obesity, its incidence continues to rise, as do the obesity related costs to society. Understanding how peptides in the brain and the periphery regulate food intake and body weight is crucial for solving the problem of obesity. Bariatric surgery is the most effective treatment to date. Although effective by restricting food intake and bypassing regions of the GI tract, recently identified gut hormones are now implicated in the effectiveness of obesity surgery. I hypothesize that signals from the ileum (GLP-1) and the melanocortin system are important components of the weight loss seen post-operatively. One aim of this proposal is to assess the role of GLP-1 produced in the ileum (through ileal transposition) as a mediator of ileal-induced weight loss. Because the melanocortin system is also critically involved in the regulation of energy balance, the second aim of this proposal is to assess the role of the central melanocortin system in the weight loss following ileal transposition surgery. Together these specific aims will help clarify the mechanisms underlying obesity surgery and may contribute to the development of more effective treatments for obesity.